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Bacteria
Bacteria cause most infectious disease Most bacteria have cell wall, which is unique to prokaryotic cells, hence representing a selective drug target. WHO maintain data sets; http://www.who.int/vaccine_research/diseases/soa_bacterial/en/index3.html A number of bacterial diseases such as tuberculosis (tubercle bacillus) http://en.wikipedia.org/wiki/Tuberculosis are a cause of concern due to increasing resistance to antibiotics, and as a secondary infection associated with HIV. Antibiotics Antibiotics are a basic treatment for most bacterial infections. Antibiotics can be described as bacteriocidal or bacteriostatic most bacteria in use are derived from natural products such as microbes or fungi, and there are many synthetic version based on these lead compounds. fluoroquinolones represent the only totally synthetic class of antibiotic Bacterial biochemistry include D-amino acids, which are not present in human biochemistry, hence are a drug target. targets and modes for antibacterial action The potential targets for antibacterial drugs are as follows # cell metabolism # inhibition of cell wall synthesis # plasma membrane # disruption of protein synthesis # inhibition of nucleaic acid transcription and replication but the main proven antibacterials target are against the following targets; # bacterial cell-wall synthesis # bacterial protein synthesis # bacterial DNA replication and repair biochemical reactions as targets for antibacterial agents Folate biosynthesis is an example of a metabolic pathway found in bacteria but not in humans, as human can obtain it from their diet. humans also maintain transport proteins to uptake folate into cells. bacterial structures as targets bacteria have a number of cellular physical features which are unique to either their species, or to eukaryotes in general which can be either attacked directly, or disrupted in their manufacture The cell wall is of particular interest, because well its right there on the outside waiting for it. And also that loss of the cell wall typically results in lysis and cell death for the bacteria. plasma membrane as an antibacterial drug target viral protein synthesis as a target nucleic acid transcription and replication nucleoside analogues antibiotic resistance Since they were introduced, many bacterial acquired antimicrobial resistance, and many patients are becoming infected by resistant strains in nosocomial settings The American Society for Microbiology Task Force on Antibiotic resistance recommand # surveillance networks to recognize emerging resistance # eduication of health professionals # basic research for developing new modes The most serious of Gram-positive organisms oxacillin-resistant Staphylococcus aweus, vancomycin-resistant enterococci penicillin-non-susceptible strepto-cocci extended-spectrum p-lactamases (ESBLs) in Klebsiella pneuruonirze or Escherichia coli and stably derepressed Bush-Jacoby-Medeiros group 1 cephalosporinases in some species of Enterobacteriaceae. coagulase-negative Oxacillin- and Multiresistant Staphylococci Glycopeptide Resistance in Enterococci glycopeptide resistance but most strains resistant to glycopeptides appear to be the result of independent genetic events theaputic index a measure of selectivity of drugs again bacterial targets @todo = Structure = bacterial envelope ;bacterial envelop: the plasma membrane and the cell wall taken together comprise the bacterial envelope. The bacteria external surface may also have flagella and capsule. cytoplasm The plasma membrane of the bacteria contains the cytoplasm, which in bacteria does not contain a nucleus, hence the DNA is in the form of a single chromosome there are also no mitochondria in bacteria Cell Wall bacterial cells have to survive varying pH and osmotic pressure, without the cell wall, osmotic pressure can cause water to flow into the cell causing it to swell, until it eventually bursts, called lysis. The cell wall acts as a physical barrier to this physical change, by preventing swelling. The bacterial cell wall is a mesh structure, "like chicken-wire" which exists outside the cell membrane. The thickness and qualities vary between species, and there is a de facto @todo? division into gram negative and gram positive. Gram was the Danish scientist. There are about 30 enzymes involved in the biosynthesis of the cell wall bacteria cell walls do not contain any sterol Animal @todo cells do not have a cell wall making it a target for antibiotics. peptidoglcycan peptidoglcycan is unique to prokaryotes and present in all bacteria except Mycoplasma the peptidoglycan cell wall contains chains of alternative NAM and NAG sugers, with cross linking chains peptide chains bound to the neighbouring NAM sugars peptide substituent with covalent bonds. peptidoglycan contains peptide and sugar, structure as parallel chains of alternating N-acetylmuramic acid (NAM) and N-acetylglucocasamine (NAG) sugars. peptide chains are bound to the NAM sugars. Gram gram positive and gram negative the gram test is a 3 stage test; # stain the cells purple # decolourize with organic solvent # stann the cells red Gram negative bacteria are easily decolourized at stage two Pg 698 Graham 2009 gram positive resist the decolourization at stage and remain purple Gram Positive have a thick cell wall, 20-40nm comprised of about 50% peptidoglycan 40-45% negatively charge acidic polymer 5-10% proteins and polysaccharides the gram postive bacteria typically has a higher osmotic pressure (~20 atm), which is contained by the cell wall, than the gram negative types the strong polar nature of the cell wall favours positively charged molecules to penetrate the cell wall Pg 622, section 50, Rand and Dales Pharmacology the gram positive bacterial cell wall has 5-100 layers Pg 432, Cp 19 Med Chem, Graham 2009 of peptidoglycan In gram-positive bacteria, the peptidoglycan molecules are cross-linked by a pentapeptide bridge, whereas in gram-negative bacteria, the peptidoglycan molecules are directly covalently bound to each other. Gram Negative # thin cell wall diagram Gram negative bacteria Pg 435 Graham 2009 complex polysaccharides on the outer surface, acting as antigens and endotoxin outer membrane containing embedded porins peptidoglycan layer (2nm thick) cell membrane the gram postive bacteria typically has a low osmotic pressure (~5 atm), which is contained by the cell wall the cell wall has 2 layers Pg 432, Cp 19 Med Chem, Graham 2009 of peptidoglycan ;endotoxins: can trigger the infammatory reaction ; porins: pores allowing the transport of small molecules Outer Membrane However gram negative bacteria also possess an outer lipopolysacheride membrane surrounding the cell wall which is also impervious to polar molecules. Penicillin in a polar molecule, which can be blocked by the gram negative outer membrane. but gram negative bacteria also possess porins, which are proteins which allow the flow of molecules, and small drugs such as penicillin drugs have less chance of passing through the porins if they are large and hydrophobic, and have negative charge. have an additional outer membrance made up of lipopolysaccharides = lifecycle = synthesis of the "main" types of macromolecule in a bacteria are broken into 3 stages # precursor # constituent # assembled into macromolecules \theta replication theta mode replication = Treatment = penicillin penicillin interferes with bacteria by preventing the formation of the bacterial cell wall, by preventing the formation of cross links by forming covalent bonds with penicillin binding proteins. resistance \beta -lactamases or penicillinases produced widespread resistance to penicillin, which in 1960 80% of S aureus infections in hospital were due to penicillin resistant strains. (Graham 2009) However further penicillinase resistant antibiotics were developed. Methicillin was the first synthetic penicillinase resistant antibiotic MRSA refers to methicillin resistant S aureus Bacterial efflux pumps ;Staphylococcus aureus:bacteria developed resistance Morphology ;cocci:spherical ;bacilli:cylindrical ;streptocci:chains ;staphylocci:clusters other antibacterial techniques Phage therapy is a technique used mainly in Georgia,; http://en.wikipedia.org/wiki/Phage_therapy book about phage therapy was recently released; lots of interest because it could be plausibly a safe and alternative strategy (complementary strategy?) to antibiotics racemase enzymes bacterial biochemistry contains bother D- and L- amino acids, and bacteria have an enzyme racemase which can convery L-Amino acids to D-amino acids.